Last data update: May 06, 2024. (Total: 46732 publications since 2009)
Records 1-11 (of 11 Records) |
Query Trace: Wilson JR[original query] |
---|
Aberrant Cellular Glycosylation May Increase the Ability of Influenza Viruses to Escape Host Immune Responses through Modification of the Viral Glycome.
Alymova IV , Cipollo JF , Parsons LM , Music N , Kamal RP , Tzeng WP , Goldsmith CS , Contessa JN , Hartshorn KL , Wilson JR , Zeng H , Gansebom S , York IA . mBio 2022 13 (2) e0298321 Individuals with metabolic dysregulation of cellular glycosylation often experience severe influenza disease, with a poor immune response to the virus and low vaccine efficacy. Here, we investigate the consequences of aberrant cellular glycosylation for the glycome and the biology of influenza virus. We transiently induced aberrant N-linked glycosylation in cultured cells with an oligosaccharyltransferase inhibitor, NGI-1. Cells treated with NGI-1 produced morphologically unaltered viable influenza virus with sequence-neutral glycosylation changes (primarily reduced site occupancy) in the hemagglutinin and neuraminidase proteins. Hemagglutinin with reduced glycan occupancy required a higher concentration of surfactant protein D (an important innate immunity respiratory tract collectin) for inhibition compared to that with normal glycan occupancy. Immunization of mice with NGI-1-treated virus significantly reduced antihemagglutinin and antineuraminidase titers of total serum antibody and reduced hemagglutinin protective antibody responses. Our data suggest that aberrant cellular glycosylation may increase the risk of severe influenza as a result of the increased ability of glycome-modified influenza viruses to evade the immune response. IMPORTANCE People with disorders such as cancer, autoimmune disease, diabetes, or obesity often have metabolic dysregulation of cellular glycosylation and also have more severe influenza disease, a reduced immune response to the virus, and reduced vaccine efficacy. Since influenza viruses that infect such people do not show consistent genomic variations, it is generally assumed that the altered biology is mainly related to host factors. However, since host cells are responsible for glycosylation of influenza virus hemagglutinin and neuraminidase, and glycosylation is important for interactions of these proteins with the immune system, the viruses may have functional differences that are not reflected by their genomic sequence. Here, we show that imbalanced cellular glycosylation can modify the viral glycome without genomic changes, leading to reduced innate and adaptive host immune responses to infection. Our findings link metabolic dysregulation of host glycosylation to increased risk of severe influenza and reduced influenza virus vaccine efficacy. |
Functional antibody-dependent cell mediated cytotoxicity (ADCC) responses to vaccine and circulating influenza strains following vaccination
Chen X , Sun HY , Lee CY , Rostad CA , Trost J , Abreu RB , Carlock MA , Wilson JR , Gansebom S , Ross TM , Steinhauer DA , Anderson EJ , Anderson LJ . Virology 2022 569 44-55 Novel cell-based assays were developed to assess antibody-dependence cellular cytotoxicity (ADCC) antibodies against both vaccine and a representative circulation strain HA and NA proteins for the 2014-15 influenza season. The four assays using target cells stably expressing one of the four proteins worked well. In pre- and post-vaccine sera from 70 participants in a pre-season vaccine trial, we found ADCC antibodies and a rise in ADCC antibody titer against target cells expressing the 4 proteins but a much higher titer for the vaccine than the circulating HA in both pre-and post-vaccine sera. These differences in HA ADCC antibodies were not reflected in differences in HA binding antibodies. Our observations suggested that relatively minor changes on the subtype HA can result in large differences in ADCC activity. |
Modification of the generalized quasi-likelihood model in the analysis of the Add Health study
Irimata KE , Wilson JR . Stat Methods Med Res 2019 29 (8) 2087-2099 The relationship between the mean and variance is an implicit assumption of parametric modeling. While many distributions in the exponential family have a theoretical mean-variance relationship, it is often the case that the data under investigation are correlated, thus varying from the relation. We present a generalized method of moments estimation technique for modeling certain correlated data by adjusting the mean-variance relationship parameters based on a canonical parameterization. The proposed mean-variance form describes overdispersion using two parameters and implements an adjusted canonical parameter which makes this approach feasible for all distributions in the exponential family. Test statistics and confidence intervals are used to measure the deviations from the mean-variance relation parameters. We use the modified relation as a means of fitting generalized quasi-likelihood models to correlated data. The performance of the proposed modified generalized quasi-likelihood model is demonstrated through a simulation study and the importance of accounting for overdispersion is highlighted through the evaluation of adolescent obesity data collected from a U.S. longitudinal study. |
Biosensor-based epitope mapping of antibodies targeting the hemagglutinin and neuraminidase of influenza A virus
Guo Z , Wilson JR , York IA , Stevens J . J Immunol Methods 2018 461 23-29 Characterization of the epitopes on antigen recognized by monoclonal antibodies (mAb) is useful for the development of therapeutic antibodies, diagnostic tools, and vaccines. Epitope mapping also provides functional information for sequence-based repertoire analysis of antibody response to pathogen infection and/or vaccination. However, development of mapping strategies has lagged behind mAb discovery. We have developed a site-directed mutagenesis approach that can be used in conjunction with bio-layer interferometry (BLI) biosensors to map mAb epitopes. By generating a panel of single point mutants in the recombinant hemagglutinin (HA) and neuraminidase (NA) proteins of influenza A viruses, we have characterized the epitopes of hundreds of mAbs targeting the H1 and H3 subtypes of HA and the N9 subtype of NA. |
An influenza A virus (H7N9) anti-neuraminidase monoclonal antibody protects mice from morbidity without interfering with the development of protective immunity to subsequent homologous challenge
Wilson JR , Belser JA , DaSilva J , Guo Z , Sun X , Gansebom S , Bai Y , Stark TJ , Chang J , Carney P , Levine MZ , Barnes J , Stevens J , Maines TR , Tumpey TM , York IA . Virology 2017 511 214-221 The emergence of A(H7N9) virus strains with resistance to neuraminidase (NA) inhibitors highlights a critical need to discover new countermeasures for treatment of A(H7N9) virus-infected patients. We previously described an anti-NA mAb (3c10-3) that has prophylactic and therapeutic efficacy in mice lethally challenged with A(H7N9) virus when delivered intraperitoneally (i.p.). Here we show that intrananasal (i.n.) administration of 3c10-3 protects 100% of mice from mortality when treated 24h post-challenge and further characterize the protective efficacy of 3c10-3 using a nonlethal A(H7N9) challenge model. Administration of 3c10-3 i.p. 24h prior to challenge resulted in a significant decrease in viral lung titers and deep sequencing analysis indicated that treatment did not consistently select for viral variants in NA. Furthermore, prophylactic administration of 3c10-3 did not inhibit the development of protective immunity to subsequent homologous virus re-challenge. Taken together, 3c10-3 highlights the potential use of anti-NA mAb to mitigate influenza virus infection. |
An influenza A virus (H7N9) anti-neuraminidase monoclonal antibody with prophylactic and therapeutic activity in vivo
Wilson JR , Guo Z , Reber A , Kamal RP , Music N , Gansebom S , Bai Y , Levine M , Carney P , Tzeng WP , Stevens J , York IA . Antiviral Res 2016 135 48-55 Zoonotic A(H7N9) avian influenza viruses emerged in China in 2013 and continue to be a threat to human public health, having infected over 800 individuals with a mortality rate approaching 40%. Treatment options for people infected with A(H7N9) include the use of neuraminidase (NA) inhibitors. However, like other influenza viruses, A(H7N9) can become resistant to these drugs. The use of monoclonal antibodies is a rapidly developing strategy for controlling influenza virus infection. Here we generated a murine monoclonal antibody (3c10-3) directed against the NA of A(H7N9) and show that prophylactic systemic administration of 3c10-3 fully protected mice from lethal challenge with wild-type A/Anhui/1/2013 (H7N9). Further, post-infection treatment with a single systemic dose of 3c10-3 at either 24, 48 or 72 h post A(H7N9) challenge resulted in both dose- and time-dependent protection of up to 100% of mice, demonstrating therapeutic potential for 3c10-3. Epitope mapping revealed that 3c10-3 binds near the enzyme active site of NA, and functional characterization showed that 3c10-3 inhibits the enzyme activity of NA and restricts the cell-to-cell spread of the virus in cultured cells. Affinity analysis also revealed that 3c10-3 binds equally well to recombinant NA of wild-type A/Anhui/1/2013 and to a variant NA carrying a R289K mutation known to infer NAI resistance. These results suggest that 3c10-3 has the potential to be used as a therapeutic to treat A(H7N9) infections either as an alternative to, or in combination with, current NA antiviral inhibitors. |
Antibody-dependent cell-mediated cytotoxicity to hemagglutinin of influenza A viruses after influenza vaccination in humans
Zhong W , Liu F , Wilson JR , Holiday C , Li ZN , Bai Y , Tzeng WP , Stevens J , York IA , Levine MZ . Open Forum Infect Dis 2016 3 (2) ofw102 Background. Detection of neutralizing antibodies (nAbs) to influenza A virus hemagglutinin (HA) antigens by conventional serological assays is currently the main immune correlate of protection for influenza vaccines However, current prepandemic avian influenza vaccines are poorly immunogenic in inducing nAbs despite considerable protection conferred. Recent studies show that Ab-dependent cell-mediated cytotoxicity (ADCC) to HA antigens are readily detectable in the sera of healthy individuals and patients with influenza infection. Methods. Virus neutralization and ADCC activities of serum samples from individuals who received either seasonal or a stock-piled H5N1 avian influenza vaccine were evaluated by hemagglutination inhibition assay, microneutralization assay, and an improved ADCC natural killer (NK) cell activation assay. Results. Immunization with inactivated seasonal influenza vaccine led to strong expansion of both nAbs and ADCC-mediating antibodies (adccAbs) to H3 antigen of the vaccine virus in 24 postvaccination human sera. In sharp contrast, 18 individuals vaccinated with the adjuvanted H5N1 avian influenza vaccine mounted H5-specific antibodies with strong ADCC activities despite moderate virus neutralization capacity. Strength of HA-specific ADCC activities is largely associated with the titers of HA-binding antibodies and not with the fine antigenic specificity of anti-HA nAbs. Conclusions. Detection of both nAbs and adccAbs may better reflect protective capacity of HA-specific antibodies induced by avian influenza vaccines. |
Diverse antigenic site targeting of influenza hemagglutinin in the murine antibody recall response to A(H1N1)pdm09 virus.
Wilson JR , Guo Z , Tzeng WP , Garten RJ , Xiyan X , Blanchard EG , Blanchfield K , Stevens J , Katz JM , York IA . Virology 2015 485 252-262 Here we define the epitopes on HA that are targeted by a group of 9 recombinant monoclonal antibodies (rmAbs) isolated from memory B cells of mice, immunized by infection with A(H1N1)pdm09 virus followed by a seasonal TIV boost. These rmAbs were all reactive against the HA1 region of HA, but display 7 distinct binding footprints, targeting each of the 4 known antigenic sites. Although the rmAbs were not broadly cross-reactive, a group showed subtype-specific cross-reactivity with the HA of A/South Carolina/1/18. Screening these rmAbs with a panel of human A(H1N1)pdm09 virus isolates indicated that naturally-occurring changes in HA could reduce rmAb binding, HI activity, and/or virus neutralization activity by rmAb, without showing changes in recognition by polyclonal antiserum. In some instances, virus neutralization was lost while both ELISA binding and HI activity were retained, demonstrating a discordance between the two serological assays traditionally used to detect antigenic drift. |
Recombinant influenza H7 hemagglutinins induce lower neutralizing antibody titers in mice than do seasonal hemagglutinins
Blanchfield K , Kamal RP , Tzeng WP , Music N , Wilson JR , Stevens J , Lipatov AS , Katz JM , York IA . Influenza Other Respir Viruses 2014 8 (6) 628-35 BACKGROUND: Vaccines against avian influenza viruses often require high hemagglutinin (HA) doses or adjuvants to achieve serological titers associated with protection against disease. In particular, viruses of the H7 subtype frequently do not induce strong antibody responses following immunization. OBJECTIVES: To evaluate whether poor immunogenicity of H7 viruses is an intrinsic property of the H7 hemagglutinin. METHODS: We compared the immunogenicity, in naive mice, of purified recombinant HA from two H7 viruses [A/Netherlands/219/2003(H7N7) and A/New York/107/2003(H7N2)] to that of HA from human pandemic [A/California/07/2009(H1N1pdm09)] and seasonal [A/Perth16/2009(H3N2)] viruses. RESULTS: After two intramuscular injections with purified hemagglutinin, mice produced antibodies to all HAs, but the response to the human virus HAs was greater than to H7 HAs. The difference was relatively minor when measured by ELISA, greater when measured by hemagglutination inhibition assays, and more marked still by microneutralization assays. H7 HAs induced little or no neutralizing antibody response in mice at either dose tested. Antibodies induced by H7 were of significantly lower avidity than for H3 or H1N1pdm09. CONCLUSIONS: We conclude that H7 HAs may be intrinsically less immunogenic than HA from seasonal human influenza viruses. |
Influenza vaccination accelerates recovery of ferrets from lymphopenia
Music N , Reber AJ , Lipatov AS , Kamal RP , Blanchfield K , Wilson JR , Donis RO , Katz JM , York IA . PLoS One 2014 9 (6) e100926 Ferrets are a useful animal model for human influenza virus infections, since they closely mimic the pathogenesis of influenza viruses observed in humans. However, a lack of reagents, especially for flow cytometry of immune cell subsets, has limited research in this model. Here we use a panel of primarily species cross-reactive antibodies to identify ferret T cells, cytotoxic T lymphocytes (CTL), B cells, and granulocytes in peripheral blood. Following infection with seasonal H3N2 or H1N1pdm09 influenza viruses, these cell types showed rapid and dramatic changes in frequency, even though clinically the infections were mild. The loss of B cells and CD4 and CD8 T cells, and the increase in neutrophils, were especially marked 1-2 days after infection, when about 90% of CD8+ T cells disappeared from the peripheral blood. The different virus strains led to different kinetics of leukocyte subset alterations. Vaccination with homologous vaccine reduced clinical symptoms slightly, but led to a much more rapid return to normal leukocyte parameters. Assessment of clinical symptoms may underestimate the effectiveness of influenza vaccine in restoring homeostasis. |
Diversity of the murine antibody response targeting influenza A(H1N1pdm09) hemagglutinin.
Wilson JR , Tzeng WP , Spesock A , Music N , Guo Z , Barrington R , Stevens J , Donis RO , Katz JM , York IA . Virology 2014 458-459 (1) 114-124 We infected mice with the 2009 influenza A pandemic virus (H1N1pdm09), boosted with an inactivated vaccine, and cloned immunoglobulins (Igs) from HA-specific B cells. Based on the redundancy in germline gene utilization, we inferred that between 72-130 unique IgH VDJ and 35 different IgL VJ combinations comprised the anti-HA recall response. The IgH VH1 and IgL VK14 variable gene families were employed most frequently. A representative panel of antibodies were cloned and expressed to confirm reactivity with H1N1pdm09 HA. The majority of the recombinant antibodies were of high avidity and capable of inhibiting H1N1pdm09 hemagglutination. Three of these antibodies were subtype-specific cross-reactive, binding to the HA of A/South Carolina/1/1918(H1N1), and one further reacted with A/swine/Iowa/15/1930(H1N1). These results help to define the genetic diversity of the influenza anti-HA antibody repertoire profile induced following infection and vaccination, which may facilitate the development of influenza vaccines that are more protective and broadly neutralizing. Importance: Protection against influenza viruses is mediated mainly by antibodies, and in most cases this antibody response is narrow, only providing protection against closely related viruses. In spite of this limited range of protection, recent findings indicate that individuals immune to one influenza virus may contain antibodies (generally a minority of the overall response) that are more broadly reactive. These findings have raised the possibility that influenza vaccines could induce a more broadly protective response, reducing the need for frequent vaccine strain changes. However, interpretation of these observations is hampered by the lack of quantitative characterization of the antibody repertoire. In this study, we used single-cell cloning of influenza HA-specific B cells to assess the diversity and nature of the antibody response to influenza hemagglutinin in mice. Our findings help to put bounds on the diversity of the anti-hemagglutinin antibody response, as well as characterizing the cross-reactivity, affinity, and molecular nature of the antibody response. |
- Page last reviewed:Feb 1, 2024
- Page last updated:May 06, 2024
- Content source:
- Powered by CDC PHGKB Infrastructure